The eukaryotic genome is highly organized within the nucleus. The long-chain of double-stranded DNA twines the histone octamer (most commonly comprising two copies of histones H2A, H2B, H3, and H4) to form nucleosomes. Then, the basic unit is further compressed by nucleus aggregation and folding to form highly condensed chromatin structure. There are a series of possible different aggregation states, and the compactness of the structure changes during the cell cycle and is most compact during the cell division process. Chromatin structure plays a key role in the regulation of gene transcription, and gene transcription cannot occur efficiently by highly condensed chromatin. The chromatin structure is controlled by a series of post-translational modifications of histones (in particular histones H3 and H4), and the modification is most often within the tail of histone, the tail extends beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. These epigenetic marks are written and erased by specific enzymes. The specific enzyme will be tagged on specific residues in the tail of the histone, thus forming an epigenetic coding, which is then interpreted by the cell to allow the gene specific regulation of chromatin structure, thus allowing the transcription.
Histone acetylation is most commonly associated with the activation of gene transcription because this modification relaxes the interaction of DNA and histone octamers by altering the electrostatic properties. In addition to this physical change, specific proteins bind to acetylated lysine residues within histones to read epigenetic coding. In the case of histones, the bromodomains are small, distinct domains within a protein that are normally but not specifically bound to acetylated lysine residues. There is a family of about 50 proteins that are known to contain bromodomains and they have a range of functions within the cell.
The bromodomain-containing protein of Bet family includes four kinds of proteins (BRD2, BRD3, BRD4, and BRD-t) having tandem bromodomain domain that can bind two closely acetylated lysine residues, thus increasing the specificity of the interaction. It has been reported that BRD2 and BRD3 bind to histones along actively transcribed genes and may be involved in promoting transcriptional extension (Leroy et al., Mol. Cell. 2008 30(1):51-60), while BRD4 seems to be involved in the recruite of pTEF-I3 complex to inducible genes, thus resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al., 2009, 138(1): 129-145). Moreover, all family members have certain functions in the control or execution of the cell cycle, and have been shown to maintain their recombination with chromosomes during cell division, which suggests their role in maintaining epigenetic memory. In addition, as part of the viral replication process, some viruses utilize these proteins to tether their genomes to the chromatin of the host cells (You et al., Cell, 2004 117(3):349-60).
Related recent articles include Trends in Molecular Medicines about BET (2014, 20(9) 477-478); Trends in Pharmacological Sciences (2012, 33(3)146-153); J. Med. Chem., (2012, 55, 9393-9413); J. Biol. Chem., (2012, 287(46):38956). Hundreds of different genetic factors are identified, many of which are chromatin-associated proteins. These associated proteins are directly related to different diseases such as cancer, neurological diseases, metabolic diseases, cardiovascular diseases, viruses, inflammation, autoimmune diseases and the like. The clinically developed bromodomain inhibitors include BMS-986158 (BMS), MRK-8628 (Merck), BAY1238097 (Bayer), INCB54329 (Incyte), etc. Therefore, the bromodomain inhibitor provided by the present invention can provide a method for controlling the pathological changes involved by the bromodomain protein.